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Andrographolide simultaneously augments Nrf2 antioxidant defense and facilitates autophagic flux blockade in cigarette smoke-exposed human bronchial epithelial cells.
Toxicol Appl Pharmacol. 2018 12 01; 360:120-130.TA

Abstract

Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens oxidative stress and impairs autophagy, advancing COPD progression. Andrographolide is a bioactive diterpenoid lactone isolated from the plant Andrographis paniculata which has been a traditional medicinal herb for respiratory diseases. As airway epithelial cells form the first interface to be exposed to cigarette smoke, this study aimed to explore the modulatory effects of andrographolide on oxidative stress and autophagy in human bronchial epithelial BEAS-2B cells exposed to cigarette smoke extract (CSE). CSE (2%) exposure increased autophagic markers p62 and LC3B-II levels in BEAS-2B cells. Andrographolide alone increased p62 and p-p62 (S349) but not LC3B-II in BEAS-2B cells. However, in the presence of CSE, andrographolide was able to simultaneously increase LC3B-II level and enhance antioxidant defense by decreasing oxidative stress and increasing total antioxidant capacity, through upregulation of nuclear Nrf2 via the p62-Nrf2 positive feedback loop. Using RFP-GFP-LC3B transfected BEAS-2B cells exposed to CSE, andrographolide was found to impair autophagosome fusion with lysosome, which may account for the moderate increase in activated caspase 3/7 and annexin V levels. Our findings revealed for the first time that andrographolide simultaneously upregulated antioxidant defense through the p62-Nrf2 loop and moderately induced apoptosis through impairment of autophagic flux in CSE-exposed bronchial epithelium. Andrographolide facilitated cigarette smoke-induced apoptosis may be a potential toxicological outcome or may protect against chronic inflammation and aberrant DNA repair. Validation of these in-vitro findings in an experimental COPD model by andrographolide is warranted.

Authors+Show Affiliations

Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600, Singapore.Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600, Singapore.Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600, Singapore.Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600, Singapore; Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga L5L 1C6, Canada.Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600, Singapore.Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, 117597, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, 117456, Singapore.Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, 117600, Singapore; Immunology Program, Life Science Institute, National University of Singapore, 28 Medical Drive, 117456, Singapore; Singapore-HUJ Alliance for Research and Enterprise (SHARE), National University of Singapore, 1 CREATE Way, Innovation Wing, 138602, Singapore. Electronic address: phcwongf@nus.edu.sg.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30291937

Citation

Tan, W S Daniel, et al. "Andrographolide Simultaneously Augments Nrf2 Antioxidant Defense and Facilitates Autophagic Flux Blockade in Cigarette Smoke-exposed Human Bronchial Epithelial Cells." Toxicology and Applied Pharmacology, vol. 360, 2018, pp. 120-130.
Tan WSD, Liao W, Peh HY, et al. Andrographolide simultaneously augments Nrf2 antioxidant defense and facilitates autophagic flux blockade in cigarette smoke-exposed human bronchial epithelial cells. Toxicol Appl Pharmacol. 2018;360:120-130.
Tan, W. S. D., Liao, W., Peh, H. Y., Vila, M., Dong, J., Shen, H. M., & Wong, W. S. F. (2018). Andrographolide simultaneously augments Nrf2 antioxidant defense and facilitates autophagic flux blockade in cigarette smoke-exposed human bronchial epithelial cells. Toxicology and Applied Pharmacology, 360, 120-130. https://doi.org/10.1016/j.taap.2018.10.005
Tan WSD, et al. Andrographolide Simultaneously Augments Nrf2 Antioxidant Defense and Facilitates Autophagic Flux Blockade in Cigarette Smoke-exposed Human Bronchial Epithelial Cells. Toxicol Appl Pharmacol. 2018 12 1;360:120-130. PubMed PMID: 30291937.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Andrographolide simultaneously augments Nrf2 antioxidant defense and facilitates autophagic flux blockade in cigarette smoke-exposed human bronchial epithelial cells. AU - Tan,W S Daniel, AU - Liao,Wupeng, AU - Peh,Hong Yong, AU - Vila,Merima, AU - Dong,Jinrui, AU - Shen,Han-Ming, AU - Wong,W S Fred, Y1 - 2018/10/04/ PY - 2018/07/25/received PY - 2018/09/30/revised PY - 2018/10/02/accepted PY - 2018/10/7/pubmed PY - 2019/4/27/medline PY - 2018/10/7/entrez KW - Apoptosis KW - Autophagic flux KW - LC3B KW - Nrf2 KW - p62 SP - 120 EP - 130 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 360 N2 - Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens oxidative stress and impairs autophagy, advancing COPD progression. Andrographolide is a bioactive diterpenoid lactone isolated from the plant Andrographis paniculata which has been a traditional medicinal herb for respiratory diseases. As airway epithelial cells form the first interface to be exposed to cigarette smoke, this study aimed to explore the modulatory effects of andrographolide on oxidative stress and autophagy in human bronchial epithelial BEAS-2B cells exposed to cigarette smoke extract (CSE). CSE (2%) exposure increased autophagic markers p62 and LC3B-II levels in BEAS-2B cells. Andrographolide alone increased p62 and p-p62 (S349) but not LC3B-II in BEAS-2B cells. However, in the presence of CSE, andrographolide was able to simultaneously increase LC3B-II level and enhance antioxidant defense by decreasing oxidative stress and increasing total antioxidant capacity, through upregulation of nuclear Nrf2 via the p62-Nrf2 positive feedback loop. Using RFP-GFP-LC3B transfected BEAS-2B cells exposed to CSE, andrographolide was found to impair autophagosome fusion with lysosome, which may account for the moderate increase in activated caspase 3/7 and annexin V levels. Our findings revealed for the first time that andrographolide simultaneously upregulated antioxidant defense through the p62-Nrf2 loop and moderately induced apoptosis through impairment of autophagic flux in CSE-exposed bronchial epithelium. Andrographolide facilitated cigarette smoke-induced apoptosis may be a potential toxicological outcome or may protect against chronic inflammation and aberrant DNA repair. Validation of these in-vitro findings in an experimental COPD model by andrographolide is warranted. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/30291937/Andrographolide_simultaneously_augments_Nrf2_antioxidant_defense_and_facilitates_autophagic_flux_blockade_in_cigarette_smoke_exposed_human_bronchial_epithelial_cells_ DB - PRIME DP - Unbound Medicine ER -